The present invention provides novel compositions of matter. In particular, the present invention provides novel substituted naphthalenes, indoles, benzofurans, and benzothiophenes which are useful as inhibitors of the synthesis of leukotrienes and as inhibitors of the action of lipoxygenase in mammalian metabolism.
The leukotrienes are a class of unsaturated fatty acid compounds which are derived from arachidonic acid by the action of lipoxygenase. See, e.g., Samuelsson, Trends in Pharmacological Sciences, 5: 227 (1980); and Samuelsson, et al., Annu. Rev. Biochem. 47: 997-1029 (1978). For a discussion of leukotriene nomenclature, see Samuelsson, et al., Prostaglandins, 19: 645 (1980).
The leukotrienes have been discovered as potent constrictors of human bronchi. That is, certain leukotrienes are mediators of the action of slow-reacting substance of anaphylaxis (SRS-A). See, e.g., Dahlen, Nature, 288: 484 (1980). These compounds are therefore important mediators of bronchoconstriction in humans.
The role of leukotrienes as agonists in immediate hypersensitivity and other pathological conditions has led to research into inhibitors of leukotriene biosynthesis and leukotriene antagonists. See, e.g., Corey, et al., Tet. Lett. 21: 4243 (1980).
Mucus secreted from submucosal glands and surface at the epithelial cells combines with water to form part of the respiratory tract secretions. In healthy states mucous secretions in the respiratory tract is normal being about 50 to 150 ml per day in man. The excessive production of mucus, however, is an important feature of many pulmonary diseases. For example, in chronic bronchitis the flow of mucus increases up to four times. The lack of the ability of the patient to deal with this hyper-production leads to paths of physiological conditions of the airways such as chronic bronchitis, asthma, and cystic fibrosis where there is a defect in consistency in clearance of the mucus. Therefore it is medically desirable to regulate the hypersecretion of mucus (J. G. Widdicobe, Brit. Med. Bull., 34: 57 (1978)). Historically, attempts have been made to treat the symptoms without regulation of the root cause. For example, mucolytics, acetylcysteine containing solutions, as well as iodides have been used. Also, antibiotics are used to treat infections in cystic fibrosis because no known drug can regulate the consistency of the mucus in this disease condition.
Leukotrienes, particularly leukotriene C.sub.4 (LTC.sub.4) and leukotriene D.sub.4 (LTD.sub.4) have been shown to be potent mucous secretagogues. Both LTC.sub.4 and LTD.sub.4 increase the release of mucus from human airways in vitro. Z. Maron, et al., Am. Rev. Respir. Dis. 126, 449-451 (1982); S. J. Coles, et al., Prostaglandins 25, 155-170 (1983) and from canine tracheas in vivo. H. G. Johnson, et al., Int. J. Immunopharmacol. 5, 178 (1983); H. G. Johnson, et al., Prostaglandins 25, 237-243 (1983). Arachidonic acid, metabolic products of arachidonic acid, monohydroxyeicosatetraenoic acid, and prostaglandins also release mucus from human airway. Z. Marom, et al., J. Clin. Invest. 67, 1695-1702 (1981). LTC.sub.4 was effective in stimulating mucus release in vivo in the cat but not in vitro on cat trachea tissue. A. C. Peatfield, et al., Br. J. Pharmac. 77, 391-393 (1982). J. H. Shelhamer, et al., Chest 81, 36S (1982) summarizes the nature of evidence available suggesting that lipoxygenase products generated by the airways in vitro might be responsible for the augmented mucus release.
O. Cromwell, et al., The Lancet, July 25, 1981, pp. 164-165, identified LTB.sub.4 and LTD.sub.4 in the sputum of cystic fibrosis patients and speculated, therefore, that inhibitors of the lipoxygenase pathway might be capable of reversing the airway obstruction in such patients.
T. Ahmed, et al., Am. Rev. Respir. Dis. 124, 110-114 (1981) demonstrated that FPL 55712, an LTC.sub.4 antagonist when given prior to antigen challenge was effective in reversing the tracheal mucus velocity in patients with a history of bronchial asthma but concluded that the clinical significance of FPL 55712 remains to be demonstrated.
In mammalian metabolism, arachidonic acid is transformed to 12-L-hydroperoxy-5,8,10,14-eicosatetraenoic acid by the action of 12-lipoxygenase. See, Hamberg, et al., Proc. Nat. Acad. Sci. 71: 3400-3404 (1974). Similarly, 5-lipoxygenase transforms arachidonic acid into 5-S-hydroperoxy-6,8,11,14-eicosatetraenoic acid. Thus, an agent which inhibits the action of lipoxygenase would be useful in treating or preventing untoward conditions associated with lipoxygenase products.
Therefore, compounds which inhibit the action of lipoxygenase are useful in the treatment of inflammatory conditions where it is desirable to prevent migration of polymorphonuclear leukocytes to the inflammatory site. They are also useful in the treatment of asthma.